An Immunologically Privileged Retinal Antigen Elicits Tolerance

Immunologically privileged retinal antigens can serve as targets of experimental autoimmune uveitis (EAU), a model for human uveitis. The tolerance status of susceptible strains, whose target antigen is not expressed in the thymus at detectable levels, is unclear. Here, we address this issue directly by analyzing the consequences of genetic deficiency versus sufficiency of a uveitogenic retinal antigen, interphotoreceptor retinoid-binding protein (IRBP). IRBP-knockout (KO) and wild-type (WT) mice on a highly EAU-susceptible background were challenged with IRBP. The KO mice had greatly elevated responses to IRBP, an altered recognition of IRBP epitopes, and their primed T cells induced exacerbated disease in WT recipients. Ultrasensitive immunohistochemical staining visualized sparse IRBP-positive cells, undetectable by conventional assays, in thymi of WT (but not of KO) mice. IRBP message was PCR amplified from these cells after microdissection. Thymus transplantation between KO and WT hosts demonstrated that this level of expression is functionally relevant and sets the threshold of immune (and autoimmune) reactivity. Namely, KO recipients of WT thymi generated reduced IRBP-specific responses, and WT recipients of KO thymi developed enhanced responses and a highly exacerbated disease. Repertoire culling and thymus-dependent CD25+ T cells were implicated in this effect. Thus, uveitis-susceptible individuals display a detectable and functionally significant tolerance to their target antigen, in which central mechanisms play a prominent role.

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Overexpressing Kallistatin Aggravates Experimental Autoimmune Uveitis Through Promoting Th17 Differentiation

Frontiers in Immunology ◽

10.3389/fimmu.2021.756423 ◽

2021 ◽

Vol 12 ◽

Author(s):

Nu Chen ◽

Shuang Chen ◽

Zhihui Zhang ◽

Xuexue Cui ◽

Lingzi Wu ◽

...

Keyword(s):

T Cells ◽

Binding Protein ◽

Wild Type ◽

Experimental Autoimmune Uveitis ◽

Autoimmune Uveitis ◽

Interphotoreceptor Retinoid Binding Protein ◽

Infectious Uveitis ◽

Ifn Γ ◽

Th17 Differentiation ◽

Experimental Autoimmune

Kallistatin or kallikrein-binding protein (KBP) has been reported to regulate angiogenesis, inflammation and tumor progression. Autoimmune uveitis is a common, sight-threatening inflammatory intraocular disease. However, the roles of kallistatin in autoimmunity and autoreactive T cells are poorly investigated. Compared to non-uveitis controls, we found that plasma levels of kallistatin were significantly upregulated in patients with Vogt-Koyanagi-Harada (VKH) disease, one of the non-infectious uveitis. Using an experimental autoimmune uveitis (EAU) model induced by human interphotoreceptor retinoid-binding protein peptide 651-670 (hIRBP651-670), we examined the effects of kallistatin on the pathogenesis of autoimmune diseases. Compared to wild type (WT) mice, kallistatin transgenic (KS) mice developed severe uveitis with dominant Th17 infiltrates in the eye. In addition, the proliferative antigen-specific T cells isolated from KS EAU mice produced increased levels of IL-17A, but not IFN-γ or IL-10 cytokines. Moreover, splenic CD4+ T cells from naïve KS mice expressed higher levels of Il17a mRNA compared to WT naïve mice. Under Th17 polarization conditions, KS mice exhibited enhanced differentiation of naïve CD4+ T cells into Th17 cells compared to WT controls. Together, our results indicate that kallistatin promotes Th17 differentiation and is a key regulator of aggravating autoinflammation in EAU. Targeting kallistatin might be a potential to treat autoimmune disease.

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Characterization of IL-17+Interphotoreceptor Retinoid-Binding Protein-Specific T Cells in Experimental Autoimmune Uveitis

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.07-0251 ◽

2007 ◽

Vol 48 (9) ◽

pp. 4153 ◽

Cited By ~ 60

Author(s):

Yong Peng ◽

Gencheng Han ◽

Hui Shao ◽

Yali Wang ◽

Henry J. Kaplan ◽

...

Keyword(s):

T Cells ◽

Binding Protein ◽

Experimental Autoimmune Uveitis ◽

Autoimmune Uveitis ◽

Interphotoreceptor Retinoid Binding Protein ◽

Experimental Autoimmune

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Autoimmune uveitis: study of treatment therapies

Einstein (São Paulo) ◽

10.1590/s1679-45082010rb1416 ◽

2010 ◽

Vol 8 (1) ◽

pp. 117-121 ◽

Cited By ~ 1

Author(s):

Alessandra Gonçalves Commodaro ◽

Luciana de Deus Vieira de Moraes ◽

Denise Vilarinho Tambourgi ◽

Rubens Belfort Jr. ◽

Osvaldo Augusto Sant’Anna ◽

...

Keyword(s):

Chronic Disease ◽

Autoimmune Disease ◽

Experimental Studies ◽

Neural Retina ◽

Experimental Autoimmune Uveitis ◽

Autoimmune Uveitis ◽

Interphotoreceptor Retinoid Binding Protein ◽

Organ Specific ◽

Retinal Antigens ◽

Experimental Autoimmune

ABSTRACT Experimental autoimmune uveitis is an organ-specific T-cell mediated autoimmune disease characterized by inflammation and consequent destruction of the neural retina and adjacent tissues. Inflammation in experimental autoimmune uveitis may be induced in rodents by immunization with retinal antigens, such as interphotoreceptor retinoid-binding protein. We present a review of experimental studies that correlate primary immunobiological functions with this chronic disease and the possible use of molecules for the treatment of autoimmune uveitis.

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Tissue-specific expression of B7x protects from CD4 T cell–mediated autoimmunity

Journal of Experimental Medicine ◽

10.1084/jem.20100639 ◽

2011 ◽

Vol 208 (8) ◽

pp. 1683-1694 ◽

Cited By ~ 44

Author(s):

Joyce Wei ◽

P’ng Loke ◽

Xingxing Zang ◽

James P. Allison

Keyword(s):

T Cells ◽

Pancreatic Islets ◽

Peripheral Tolerance ◽

Wild Type ◽

Autoimmune Encephalomyelitis ◽

Specific Expression ◽

Tissue Specific ◽

Disease Induction ◽

Deficient Mice ◽

Experimental Autoimmune

B7x, an inhibitory member of the B7/CD28 superfamily, is highly expressed in a broad range of nonhematopoietic organs, suggesting a role in maintaining peripheral tolerance. As endogenous B7x protein is expressed in pancreatic islets, we investigated whether the molecule inhibits diabetogenic responses. Transfer of disease-inducing BDC2.5 T cells into B7x-deficient mice resulted in a more aggressive form of diabetes than in wild-type animals. This exacerbation of disease correlated with higher frequencies of islet-infiltrating Th1 and Th17 cells. Conversely, local B7x overexpression inhibited the development of autoimmunity, as crossing diabetes-susceptible BDC2.5/B6g7 mice to animals overexpressing B7x in pancreatic islets abrogated disease induction. This protection was caused by the inhibition of IFN-γ production by CD4 T cells and not to a skewing or expansion of Th2 or regulatory T cells. The suppressive function of B7x was also supported by observations from another autoimmune model, experimental autoimmune encephalomyelitis, in which B7x-deficient mice developed exacerbated disease in comparison with wild-type animals. Analysis of central nervous system–infiltrating immune cells revealed that the loss of endogenous B7x resulted in expanded Th1 and Th17 responses. Data from these two autoimmune models provide evidence that B7x expression in the periphery acts as an immune checkpoint to prevent tissue-specific autoimmunity.

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Impairment of TGF-β signaling in T cells increases susceptibility to experimental autoimmune hepatitis in mice

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00286.2002 ◽

2003 ◽

Vol 284 (3) ◽

pp. G525-G535 ◽

Cited By ~ 39

Author(s):

Christoph Schramm ◽

Martina Protschka ◽

Heinz H. Köhler ◽

Jürgen Podlech ◽

Matthias J. Reddehase ◽

...

Keyword(s):

T Cells ◽

Transgenic Mice ◽

Autoimmune Hepatitis ◽

Mononuclear Cells ◽

Dominant Negative ◽

Wild Type ◽

Histological Score ◽

Tgf Β1 ◽

Increased Susceptibility ◽

Experimental Autoimmune

In autoimmune hepatitis, strong TGF-β1 expression is found in the inflamed liver. TGF-β overexpression may be part of a regulatory immune response attempting to suppress autoreactive T cells. To test this hypothesis, we determined whether impairment of TGF-β signaling in T cells leads to increased susceptibility to experimental autoimmune hepatitis (EAH). Transgenic mice of strain FVB/N were generated expressing a dominant-negative TGF-β type II receptor in T cells under the control of the human CD2 promoter/locus control region. On induction of EAH, transgenic mice showed markedly increased portal and periportal leukocytic infiltrations with hepatocellular necroses compared with wild-type mice (median histological score = 1.8 ± 0.26 vs. 0.75 ± 0.09 in wild-type mice; P < 0.01). Increased IFN-γ production (118 vs. 45 ng/ml) and less IL-4 production (341 vs. 1,256 pg/ml) by mononuclear cells isolated from transgenic livers was seen. Impairment of TGF-β signaling in T cells therefore leads to increased susceptibility to EAH in mice. This suggests an important role for TGF-β in immune homeostasis in the liver and may teleologically explain TGF-β upregulation in response to T cell-mediated liver injury.

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Bispecific T-Cell Engager -Armored Chimeric Antigen Receptor T Cells Overcome Antigen Escape From EGFRvIII-Targeted Therapy For Glioblastoma

Neurosurgery ◽

10.1093/neuros/nyz310_154 ◽

2019 ◽

Vol 66 (Supplement_1) ◽

Author(s):

Bryan D Choi ◽

Xiaoling Yu ◽

Ana P Castano ◽

Amanda A Bouffard ◽

Andrea Schmidts ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Human Skin ◽

Immune Therapy ◽

Biologically Active ◽

Target Antigen ◽

Wild Type ◽

Car T Cells ◽

Car T ◽

The Brain

Abstract INTRODUCTION Immune therapy with T cells engineered to express chimeric antigen receptors (CARs) represents a promising therapy for patients with glioblastoma (GBM). However, clinical responses have been limited due to heterogeneous target antigen expression and outgrowth of tumors lacking the antigen targeted by CAR T cells directed against a single target. In clinical studies with CART-EGFRvIII, EGFRvIII-targeted T cells successfully localized to the brain tumor microenvironment, but ultimately failed to prevent disease progression with post-treatment specimens demonstrating high levels of wild-type EGFR despite reduced expression of EGFRvIII. METHODS We developed a novel bicistronic CAR construct engineered for local delivery of bispecific T-cell engagers (BiTEs) that target residual tumor. Specifically, EGFRvIII-targeted CAR T cells were engineered to secrete BiTEs against wild-type EGFR, which is frequently amplified and overexpressed in GBM. RESULTS Human T cells were efficiently transduced with the dual CART.BiTE transgene. These modified cells secreted biologically active EGFR-specific BiTEs that not only redirected CAR T cells but also recruited and activated untransduced bystander T cells against wild-type EGFR. Recapitulating clinical data, EGFRvIII CAR T cells were unable to completely treat tumors with heterogenous EGFRvIII expression, leading to outgrowth of EGFRvIII-negative, EGFR-positive GBM. Conversely, CART.BiTE cells cured mice even in the setting of antigen-loss, against heterogeneous and well-established intracerebral tumors in mice. Unlike CAR T cells directly targeting EGFR, which caused toxicity in human skin grafts in vivo, secreted BiTE-EGFR was both locally effective and did not result in toxicity against grafted human skin. CONCLUSION This is the first instance in which CARs and BiTEs have been combined into a single platform of immune therapy. Our results demonstrate that CARs and BiTEs can be combined strategically to mitigate antigen heterogeneity in GBM and also provide a unique T-cell-based delivery method for BiTEs to tumors in the brain.

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